Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling
文献类型：期刊论文
| 作者 | Qiao, Huarui1,2,3; Hu, Fangzheng1; Wang, Yiang4; Wang, Lu4; Zhou, Siyu4; Guo, Shaojue4,5; Xu, Yiwen4,5; Xu, Jianfeng5; Cui, Qianqian4; Yang, Qilun6 |
| 刊名 | NATURE COMMUNICATIONS
 |
| 出版日期 | 2025-07-07 |
| 卷号 | 16期号:1页码:11 |
| DOI | 10.1038/s41467-025-61545-z |
| 英文摘要 | The Wnt/beta-catenin pathway requires precise regulation for proper development and tissue homeostasis, yet the structural mechanisms enabling its fine-tuned control remain incompletely understood. Here, we reveal how LGR4 achieves differential signaling outcomes through distinct recognition of two key modulators: Norrin and R-spondins (RSPOs). Using cryo-electron microscopy, we determined the structure of full-length LGR4 bound to Norrin in a 2:2 stoichiometry, revealing a molecular bridging mechanism where Norrin dimer connect two LGR4 protomers in a spatial arrangement fundamentally distinct from the LGR4-RSPO2-ZNRF3 complex. Notably, Norrin binding to LGR4 sterically hinders simultaneous interaction with the Frizzled4 receptor, establishing a regulatory checkpoint in Wnt signaling. The partially overlapping binding sites for Norrin and RSPOs on LGR4 enable mutually exclusive interactions that drive distinct signaling outcomes. Disease-linked mutations map to distinct functional regions: those disrupting LGR4 interaction are associated with familial exudative vitreoretinopathy (FEVR), while others impairing Frizzled4 binding are linked to Norrie disease. Furthermore, we developed a high-affinity nanobody that blocks both Norrin and RSPO binding to LGR4, providing a potential tool for therapeutic intervention. These findings elucidate the structural basis of LGR4's dual signaling roles and lay the groundwork for therapeutic strategies targeting Wnt-related diseases. |
| WOS关键词 | RETINAL VASCULAR DEVELOPMENT ; R-SPONDIN RECOGNITION ; CRYSTAL-STRUCTURE ; WNT RECEPTORS ; DISEASE GENE ; MUTATIONS ; COMPLEX ; LIGAND ; RNF43 ; SELECTIVITY |
| 资助项目 | Shanghai Institute of Materia Medica, Chinese Academy of Sciences |
| WOS研究方向 | Science & Technology - Other Topics |
| 语种 | 英语 |
| WOS记录号 | WOS:001524323400025 |
| 出版者 | NATURE PORTFOLIO |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/321066]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Xu, H. Eric; Zhu, Jianwei; Geng, Yong |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Engn Res Ctr Cell & Therapeut Antibody, Sch Pharm, Minist Educ, Shanghai, Peoples R China 2.Lingang Lab, Shanghai, Peoples R China 3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 4.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 5.Shanghai Ocean Univ, Coll Food Sci & Technol, Dept Biopharmaceut, Shanghai, Peoples R China 6.Shanghai Kailuo Biotechnol Co Ltd, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Qiao, Huarui,Hu, Fangzheng,Wang, Yiang,et al. Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling[J]. NATURE COMMUNICATIONS,2025,16(1):11. |
| APA | Qiao, Huarui.,Hu, Fangzheng.,Wang, Yiang.,Wang, Lu.,Zhou, Siyu.,...&Geng, Yong.(2025).Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling.NATURE COMMUNICATIONS,16(1),11. |
| MLA | Qiao, Huarui,et al."Distinct structural mechanisms of LGR4 modulation by Norrin and RSPOs in Wnt/β-catenin signaling".NATURE COMMUNICATIONS 16.1(2025):11. |
入库方式： OAI收割
来源：上海药物研究所
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